Updated Perinatal Guidelines

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Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States

Zidovudine was shown to be mutagenic in two in vitro assays and clastogenic in one in vitro and two in vivo assays, but not cytogenic in a single-dose in vivo rat study. Long-term carcinogenicity studies have been performed with zidovudine in mice and rats.1 In mice, 7 late-appearing (>19 months) vaginal neoplasms (5 non-metastasizing squamous cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of an animal given an intermediate dose. No vaginal tumors were found at the lowest dose. In rats, 2 late-appearing (>20 months), non-metastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug-related tumors were observed in either sex in either species. At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by area under the curve [AUC]) was approximately three times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every 4 hours. How predictive the results of rodent carcinogenicity studies may be for humans is unknown.

Two transplacental carcinogenicity studies were conducted in mice.2,3 In 1 study, zidovudine was administered at doses of 20 mg/kg/day or 40 mg/kg/day from gestation Day 10 through parturition and lactation, with postnatal dosing continuing in offspring for 24 months.3 The drug doses administered in this study produced zidovudine exposures approximately three times the estimated human exposure at recommended doses. After 24 months, an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. In a second study, zidovudine was administered at maximum tolerated doses of 12.5 mg/day or 25 mg/day (~1000 mg/kg non-pregnant body weight or ~450 mg/kg of term body weight) to pregnant mice from Days 12 to 18 of gestation.2 There was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher dose of zidovudine.

Reproduction/Fertility

When administered to male and female rats at doses up to seven times the usual adult dose based on body surface area, zidovudine had no effect on fertility, as judged by rates of conception.

Zidovudine has been shown to have no effect on reproduction or fertility in rodents. A dose-related cytotoxic effect on pre-implantation mouse embryos can occur, with inhibition of blastocyst and post-blastocyst development at zidovudine concentrations similar to levels achieved with human therapeutic doses.4

Teratogenicity/Developmental Toxicity

Oral teratology studies in the rat and in the rabbit at doses up to 500 mg/kg/day revealed no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal toxicity, as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or 450 mg/kg/day and rabbits given 500 mg/kg/day. The doses used in the teratology studies resulted in peak zidovudine plasma concentrations (after one-half of the daily dose) in rats 66 to 226 times and in rabbits 12 to 87 times mean steady-state peak human plasma concentrations (after one-sixth of the daily dose) achieved with the recommended daily dose (100 mg every 4 hours). In an in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted in a dose-dependent reduction in blastocyst formation. In an additional teratology study in rats, a dose of 3,000 mg/kg/day (very near the oral median lethal dose in rats of 3,683 mg/kg) caused marked maternal toxicity and an increase in incidence of fetal malformations. This dose resulted in peak zidovudine plasma concentrations 350 times peak human plasma concentrations (estimated AUC in rats at this dose level was 300 times the daily AUC in humans given 600 mg/day). No evidence of teratogenicity was seen in this experiment at doses of 600 mg/kg/day or less.

Increased fetal resorption occurred in pregnant rats and rabbits treated with zidovudine doses that produced drug plasma concentrations 66 to 226 times (rats) and 12 to 87 times (rabbits) the mean steady-state peak human plasma concentration following a single 100-mg dose of zidovudine. No other developmental anomalies were reported. In another developmental toxicity study, pregnant rats received zidovudine up to near-lethal doses that produced peak plasma concentrations 350 times peak human plasma concentrations (300 times the daily AUC in humans given 600 mg/day zidovudine). This dose was associated with marked maternal toxicity and an increased incidence of fetal malformations. However, there were no signs of teratogenicity at doses up to one-fifth the lethal dose.

In humans, in the placebo-controlled perinatal trial PACTG 076, the incidence of minor and major congenital abnormalities was similar between zidovudine and placebo groups and no specific patterns of defects were seen.5,6 Similarly, no increase in birth defects was detected among infants enrolled in the large observational cohorts, PACTG 219/219C and P1025.7,8 A previous report from the Women and Infants Transmission Study described a 10-fold increased risk of hypospadias, but this finding was not confirmed in a more detailed analysis.9,10 In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to zidovudine have been monitored to be able to detect at least a 1.5-fold increased risk of overall birth defects and a 2-fold increased incidence of defects in the more common classes, including the genitourinary system. No such increase in birth defects has been observed with zidovudine. With first-trimester zidovudine exposure, the prevalence of birth defects was 3.3% (124 of 3,789 births; 95% CI, 2.7% to 3.9%) compared with a total prevalence in the U.S. population of 2.7%, based on CDC surveillance.11

Placental and Breast Milk Passage

Zidovudine rapidly crosses the human placenta, achieving cord-to-maternal-blood ratios of about 0.80. The ratio of zidovudine in amniotic fluid to that in maternal plasma is 1.5.12 Zidovudine is excreted into human breast milk with breast milk-to-maternal-plasma zidovudine concentration ranging from 0.44 to 0.77.13,14 No zidovudine was detectable in the plasma of the nursing infants, who received zidovudine only via breast milk.

Human Studies in Pregnancy

Zidovudine is well tolerated in pregnancy at recommended adult doses and in the full-term neonate at 2 mg/kg body weight orally every 6 hours.5,15 Long-term data on the safety of in utero drug exposure in humans are not available for any antiretroviral drug; however, short-term data on the safety of zidovudine are reassuring. In PACTG 076, no difference in disease progression was seen between women who received zidovudine and those who received placebo, based on follow-up through 4 years postpartum.16 Additionally, no differences in immunologic, neurologic, or growth parameters were seen between infants with in utero zidovudine exposure and those who received placebo, based on nearly 6 years of follow-up.6,17